Hormone replacement therapy (HRT) is a medical treatment that involves the use of one or more of a group of medications designed to increase hormone levels in women who lack adequate hormone production. HRT can mitigate and prevent symptoms caused by diminished circulating estrogen and progesterone hormones regardless as to whether the subject is pre-menopausal, peri-menopausal, menopausal or post-menopausal. However, specific disease states can exist during each stage of menopausal progression.
HRT via transdermal delivery is presently available in various forms. One therapy involves administration of one or more estrogens. Another involves administration of a chemical analogue of naturally occurring progesterone, called a progestin. Progesterone administration acts, in addition to treating other disease states, to mitigate certain undesirable side effects from estrogen administration including, for example, endometrial hyperplasia (thickening), and reducing the incidence of endometrial cancer.
Reference to progesterone, both naturally-occurring and bio-identical, is generally collectively referred to herein as “progesterone.”
Various references generally suggest the use of the progestogen class of hormones for inclusion in transdermal therapies, typically in combination with an estrogen. The teachings within such references are generally limited to progestins however. Progestins are sometimes confused in the literature with progesterone or progestogens generally. Yet progestins are a distinct subclass of progestogens; a synthetic progestogen that has progestational effects similar to progesterone. Typically, synthetic progestins have higher activity and are administered at significantly lower dosages relative to natural progesterone.
The term “progestogen(s),” as used herein, is inclusive of naturally-occurring and bio-identical progesterone and all synthetic progestins. The term “bio-identical” hormones, as used herein, refers to hormones which are identical in chemical structure to the hormones naturally produced by mammals, including humans, and can be used, and are often referred to as, natural hormone replacement therapy, or “NHRT.”
Prevailing transdermal patch technologies utilize progestins over progesterone. This is due to, among others, the difficulty with solubilizing natural progesterone which is relatively insoluble, particularly at high dosages. Solubilized drug substances are preferred in the manufacture of the various patch technologies, particularly matrix and reservoir technologies. Synthetic progestins typically have greater potency and therefore lower dosage requirements. The reduced amount of progestin drug substance relative to a given volume of drug product generally affords relatively easier formulation solubility. For example, a drug load of 2.7 mg of northethindrone acetate is provided within a 9 square cm round CombiPatch® product; a drug load of 4.8 mg of norethindrone acetate within the 16 square cm patch product.
Progesterone, on the other hand, is defined by a lower potency and therefore a higher dosage requirement. A much larger amount of progesterone drug substance is required, up to 200 mg, in a patch product. Given the higher dosage requirements and relative insolubility of progesterone, no transdermal patch employing a natural progesterone drug substance has been successfully commercialized.
Considering the current trend towards natural and bio-identical products, particularly with human hormones, the present disclosure provides, among other aspects, solubilized progesterone that can be used with transdermal patch technologies, and transdermal patches comprising progesterone, alone or in combination with at least one estrogen drug substance including, without limitation, estradiol, and other drug substances having estradiol or estradiol-like biological activity that are well known in the art.
Timing for HRT dosage administration is often varied cyclically, with estrogens taken daily and progesterone taken for approximately two weeks of every month; a method often referred to as “cyclic-sequential” or “sequentially-combined” HRT. This method is intended to mimic the natural menstrual cycle and typically causes menstruation similar to a period after the progesterone is stopped. This regime is most typically used in peri-menopausal or newly menopausal women as the alternative continuous method often resulting in irregular bleeding. An alternate method involving a constant dosage with both estrogen and progesterone delivered daily is called “continuous-combined” HRT. This method usually results in no menstruation and is used most often after a woman has been menopausal for some time.
With each of the cyclic-sequential or continuous combined methods, each of an estrogen and progesterone, as used herein, may be administered in the same or different dosage forms. When used in the same dosage form, the present disclosure includes each of an estrogen and progesterone in a transdermal patch. When administered in different dosage forms, the present disclosure provides for progesterone administered in a transdermal patch.
There is also a need for a pre-packaged cyclic-HRT with combination estrogen and progesterone. By way of example, doctors desiring to prescribe cyclic-HRT are required to prescribe two separate products, namely, an estrogen patch and a combination estrogen/progesterone patch or an estrogen patch along with another form of progesterone including oral or topical. Such separate dosing regimes often result in poor patient compliance due to, among others, confusion as to how and when to take each of the medications throughout the prescribed therapy period. Increased patient morbidity may result.